Glial Cells and Polyamine Signaling in the Central Nervous System

项目摘要/摘要(来自母公司赠款)： 最近新出现的出版物表明，多胺(PA)是非常常见的 衰老障碍和艾滋病毒相关神经认知障碍(手)、阿尔茨海默氏症、亨廷顿氏症和 帕金森病以及斯奈德-罗宾逊综合征和芝麻/东方综合征。PA被整体释放 在神经元活动和创伤期间来自未知来源的大脑。PAS显示出神经保护作用 神经毒性、脑缺血、脑损伤，还可延长寿命。由于PA含量随着时间的推移或在 病理上，PAS提供的神经保护也会下降。这大大增加了 发病率和死亡率。尽管PA对公众健康具有重要意义，但人们对PA在大脑中的通量知之甚少 而对中枢神经系统内的神经胶质细胞关注不够。 有趣的是，我们发现，在健康的成人大脑和视网膜中，神经胶质细胞而不是神经元积累。 首选PAS，如亚精胺(SD)和精胺(SP)。我们最近进一步发现，PA是 星形细胞连接蛋白-43(Cx43)缝隙连接的主要开放因子。因此，由于Cx43 GJS是主要的 星形胶质细胞之间的沟通渠道，PAS保持神经胶质合体的完整性，这可能有助于保持健康 大脑状态，然而，在许多(病理)生理条件下，这种情况并没有得到很好的研究。 体内PA的储存及其受胶质细胞调节对大脑功能的影响是一些 剩下的谜团和我们的发现提出了关键问题：(I)这种现象背后的机制是什么 PAS在星形胶质细胞和神经元之间的不均匀分布和积聚？(Ii)机制为何 中枢神经系统神经胶质细胞释放PA的能力？(Iii)脑内PA流量对神经元的影响是什么 功能呢？以及(Iv)最终，Pas在大脑紊乱和疾病中的作用是什么？ 到目前为止，胶质细胞PA通路一直被忽视，尽管这些分子显然是关键 大脑正常状态的因素及其代谢紊乱显然会导致许多 病理症状和疾病。我们已经开发了测量脑片中PA通量的技术 和视网膜，并将使用手的转基因动物模型(以及在未来的其他疾病)来研究 PA易位的(病理)生理学。在这个项目中，我们将检验最初的假设，即PA是新奇的 “神经胶质递质”：(I)运输到神经胶质细胞，(Ii)开放的星形细胞间缝隙连接，(Iii) 在星形胶质细胞-星形胶质细胞合体中增殖(AIM-1)和(IV)在局部刺激下从胶质细胞中释放 (V)调节神经元-神经胶质网络(AIM-2)。 我们将解决这两个目标，以确定PA摄取/积累/释放/信号转导的机制 中枢神经系统。这些研究将为研究生带来新的科学知识和研究机会 进一步了解神经退行性变过程，有助于推进诊断、治疗和预防。

Project Summary/Abstract (from Parent grant): Emerging recent publications show that polyamines (PAs) are key players in the exceedingly common disorders of aging and HIV associated neurocognitive disorders (HAND), Alzheimer's, Huntington's and Parkinson diseases as well as in Snyder-Robinson and SeSAME/EAST syndromes. PAs are released in whole brain from unknown sources during neuronal activity and trauma. PAs demonstrate neuroprotection against neurotoxicity, ischemia, brain injury and also increase longevity. Since PA content declines with aging or during pathology, the neuroprotection afforded by PAs can decline as well. This substantially increases the risk of morbidity and mortality. Despite its public health importance, relatively little is known about PA fluxes in brain and insufficient attention is paid to glial cells in CNS. Intriguingly, we found that in healthy adult brain and retina, glial cells but not neurons accumulate preferentially PAs such as spermidine (SD) and spermine (SP). We further recently found that PAs are the major openers of astrocytic connexin-43 (Cx43) gap junctions (GJs). Therefore, since Cx43 GJs are the major communicating channels between astrocytes, PAs keep glial syncytium integrity that may help to hold healthy brain status, however in many (patho)physiological conditions the situations are not well studied. The storage of internal PAs and their effects regulated by glia on brain function are some of the remaining mysteries and our findings raise key questions: (i) What are the mechanisms that underlie such uneven distribution and accumulation of PAs between astrocytes and neurons? (ii) What are the mechanisms of PA release in CNS from glia? (iii) What are the consequences of PA fluxes within the brain on neuronal function? and (iv) Ultimately, what are the roles of PAs in brain disorders and diseases? The glial PA pathways hitherto have been neglected, although it is evident that these molecules are key elements for normal brain status and their metabolic disorders, apparently, cause the development of many pathological syndromes and diseases. We have developed techniques for measuring PA fluxes in brain slices and retina and will use transgenic animal models of HAND (and in the future of other diseases) to study (patho)physiology of PA translocation. In this project, we will test the original hypothesis that PAs are novel “gliotransmitters” that (i) are transported into glia, (ii) open astrocytic intercellular gap junctions, (iii) propagate in the astrocyte-to-astrocyte syncytium (AIM-1) and (iv) are released from glia upon local stimulation (v) to regulate the neuronal-glial network (AIM-2). We will address these two aims to determine mechanisms of PA uptake/accumulation/release/signaling in CNS. The studies will lead to new scientific knowledge and research opportunities for graduate students to further understand neurodegenerative processes, helping advance diagnosis, treatment and prevention.